It is known that technetium(Tc)-99m (99mTc), as a radionuclide, has desirable nuclear properties, for example, a short half-life of 6 hours and 140 keV gamma ray emission energy suitable for obtaining gamma image, as well as a low price and a general utility, thus is commonly applied in nuclear medicine as radiopharmaceuticals for diagnosis and therapy. Tc-99m forms a stable complex with a compound having an unshared electron, such as isocyanate, amine, carboxy or thiol groups, and is thus used as an imaging agent or a radiolabelling agent for organs including lungs, liver and brain, or their tissues.
As isotopes of rhenium(Re), which is an analogous atom to Tc-99m, rhenium(Re)-186 (186Re) and rhenium-188 (188Re) are well known. The rhenium isotopes emit both beta ray suitable for therapy and gamma ray capable of imaging organs or living tissues. In practice, rhenium-186 and rhenium-188 are applied for alleviating pain in bone caused by secondary transition of various cancers, including prostate gland cancer, lung cancer and breast cancer, to bone. In addition, since Re-186 and Re-188 have similar chemical properties to technetium-99m, they can be applied for the radiolabelling methods using rhenium through improvement of the radiolabeling methods using Tc-99m (Lin, W. et al., Eur. J. Nucl. Med. 1997, 24, 590-595; Lewington, V. J. et al., Eur. J. Nucl. Med. 1993, 20, 66-74; Lewington, V. J. et al., Phys. Med. Biol. 1996, 41, 2027-2042; Hashimoto, K. et al., Appl. Radiat. Isot. 1996, 47, 195-199).
Using the metals technetium or rhenium, a target compound can be labeled through a process of forming a complex of a ligand with technetium or rhenium, and then performing a substitution reaction with another ligand. For example, when a lyophilized glucoheptonate is reacted with 99mTc-sodium pertechnetate, 99mTc-glucoheptonate complex is formed, and an active site of the complex is demonstrated to be [Tcv=O]3+ (Owunwanne, A. et al., The Handbook of Radiopharmaceuticals, Chapman & Hall Medical, London, UK, p. 94-95)
Based on this finding, production of technetium-labeled complex and its structure can be identified by performing a transchelation reaction with another ligand having an affinity higher than the bound ligand, glucoheptonate, and then by confirming a peak at a homologous position to [Tcv=O]3+ through thin layer chromatography (TLC) or reverse-phase high performance liquid chromatograph (HPLC).
Also, there was another attempt to form 99mTcNCl4− precursor, where pertechnetate or perrhenate is refluxed with sodium azide (NaN3) in the presence of strong HCl to form 99mTcNCl4− complex, and [99mTcv≡N]2+ complex may be formed via a ligand-exchange reaction from the complex 99mTcNCl4− (John Baldas and John Bonnyman Int. J. Appl. Radiot. Isot., 1985, 36, 133-139; Florian Demaimay, Leontine Dazord, Alain Roucoux, Nicolas Noiret, Herri Patin and Annick Moisan, Nuclear Medicine & Biology, 1997, 24, 701-705).
In addition, Alberto, et al. disclose that 99mTc-tricarbonyl complex of the low oxidation state(+1), a precursor which may be used in radiolabeling biomaterials, can be formed (Alberto R. et al., J. Am. Chem. Soc., 1998, 120, 7987-7988; Egli A. et al., J. Nucl. Med., 1999, 40(11), 1913-1917; Alberto R. et al., Radiochimica Acta., 1997, 79, 99-103; Alberto R. et al., J. Organometallic Chem., 1995, 493, 119-127; Reisgys M. et al., Bioorganic & Medicinal Chemistry Letters, 1997, 7(17), 2243-2246).
As described above, technetium or rhenium should be reduced prior to reaction of pertechnetate or perrhenate with a ligand to form complexes.
The reduction of Tc or Re may be achieved by electrolysis, or mostly in the presence of a reducing agent, including SnCl2.2H2O, ferrous ion, ferrous-ascorbate, formamidinesulphinic acid and sodium borohydride. The most commonly used reducing agent is tin chloride dihydrate (SnCl2.2H2O)
However, the reducing agent described above, tin chloride dihydrate (SnCl2.2H2O) is stable in an acidic condition, but it induces formation of precipitates in an alkaline condition. In contrast, sodium borohydride is stable at high pH, while being unstable at low pH. In addition, the reducing agents described above are typically utilized in a liquid state, when they are used excessively, impurities such as colloids can be generated, in addition to a danger of potentially residual toxicity, thereby limiting the amount of used reducing agents. These problems can be overcome through employment of a borohydride exchange resin to which borohydride ion (BH4−) is bound, with which the metal Tc or Re is reduced in a solid phase, and after that, borohydride ion can be removed by filtration, regardless of its used amount.
Because the reduction of Tc or Re has been achieved in stringent conditions as described above, there is a need for developing methods capable of reducing pertechnetate or perrhenate in a wide range of pH 2 to 14.
Leading to the present invention, the intensive and thorough research into a reducing agent for preparation of technetium or rhenium complex for radiopharmarceuticals, with the aim of solving the problems of the conventional reducing agents, resulted in the finding that technetium or rhenium complex with high radiochemical purity and excellent labeling efficiency is prepared by reacting pertechnetate or perrhenate with a ligand in the presence of borohydride exchange resin as a reducing agent.